World J. Surg. 18, 522-528, 1994 O WORLD Journal of SURGERY 9 1994 by the Soci~t~ Internationale de Chirurgie Radioiodine-Associated Thyroid Cancers Serdar Tezelman, M.D., z Richard F. Grossman, M.D., 1 Allan E. Siperstein, M.D., 10rlo H. Clark, M.D. 1 ~Surgical Service, University of California-San Francisco/Mount Zion Medical Center, 1600 Divisadero Street, San Francisco, California 94115, U.S.A. 2Department of Surgery, University of California-San Francisco, 1600 Divisadero Street, San Francisco, California, 94115 U.S.A. 3Department of Surgery, Istanbul Faculty of Medicine, Istanbul, Turkey Abstract: Numerous investigations document that exposure to low dose external therapeutic radiation leads to the development of benign and malignant thyroid neoplasms. There is considerable controversy, how- ever, concerning whether radioactive iodine (~31I)causes thyroid cancer. The aim of this investigation was to examine our experience and that in the literature related to this problem. From 1982 to March 1993 seven of 373 patients (1.9%) with thyroid cancer who were treated hy one surgeon had a history of treatment with radioactive iodine for Graves' disease and toxic nodular goiter. Sixty-fivepatients have previously been reported in the literature from 1957 to present. Our patients (five women, two men) ranged in age from 26 to 80 years (mean 57 years). The interval between the exposure to the internal radiation and development of cancer ranged from 3 to 29 years (mean 11.4 years), and the mean age at the time of 131I treatment was 45 years (18-76 years). The therapeutic dose of 131Iwas 5 to 100 mCi (mean 25.3 mCi) in our patients. Two of our patients received 131Itwice. The age of patients reported in the literature at the time of ~31I treatment ranged from 7 to 74 years (mean 48 years). The mean therapeutic dose of 131I was 20.6 mCi (1.25-180.0 mCi) and the latent period was documented for a mean 8.7 years (0.25-28.0 years) in these patients. Three of 29 patients in the literature received ~3~I twice. Fine-needle aspiration cytologyof thyroid nodules was positive for cancer in six of our patients (86%). All patients were treated by total thyroidec- tomy, and three of them had a modified neck dissection. Six of our seven patients had invasive papillary thyroid carcinoma (stage IIl disease), and the seventh patient had extensive nodal metastasis and intrathyroidal invasion. Invasion into adjacent muscle and soft tissue were found in four patients, and two had tracheal invasion. Two patients had lymph node metastases. There were no postoperative complications. One patient (14%), however developed recurrent papillary and anaplastic thyroid cancer in his left neck and mediastinum 2 years after total thyroidectomy. He had extensive pulmonary metastases and malignant pleural effusions and died 23 days after a left modified radical neck dissection. In conclusion, radioactive iodine in doses to treat Graves' disease may increase the risk of developing thyroid cancer. These cancers are discov- ered at a later stage and appear to be aggressive. Exposure to low dose ionizing external therapeutic radiation is known to cause both benign and malignant thyroid neoplasms [1-6]. The risk of developing a cancer has been calculated to be 4.3 cancers per rem year per 106 persons exposed to radiation [7]. Most thyroid cancers occur in patients exposed to between 250 and 1500 to 2000 rad of external radiation, but as little as 7 rad increases the incidence of thyroid cancer [8, 9]. Thyroid Correspondence to: O.H. Clark, M.D. cancers appear within 3 to 5 years after radiation exposure, with the peak incidence occurring between 15 and 25 years [9]. There is considerable controversy whether internal radiation caused by radioactive iodine (131I) also increases the risk of thyroid cancer. Doniach [10] and Goldberg and Chaikoff [11] reported that administration of small doses of 131I to rats caused benign and malignant thyroid neoplasms. Prinz et al. [12] documented that administration of low doses of 13q leads to an increased frequency of thyroid tumor formation and that hypersecretion of thyrotropin seemed to be responsible. Nichols et al. [13] had previously reported that treatment of rats with thyroid hormone decreased the number of thyroid cancers that developed in the irradiated animals. Some endocrinologists deny any relation between radioiodine treatment and the development of thyroid cancers [14, 15], whereas others accept it as a rare cause [16]. Since 1957, there have been 65 patients reported to have developed thyroid cancer after receiving radioiodine (131I) treatment for hyperthyroidism [17--44]. Although the coexist- ence of thyroid cancer and hyperthyroidism has been reported to occur in 0.15% to 8.0% of patients having thyroidectomy [45, 46], there is no documented cause-effect relation between radioiodine therapy for hyperthyroidism and the subsequent development of thyroid cancer. Dobyns et al. [14], in a study of 21,714 patients, documented that benign thyroid tumors devel- oped more frequently in patients treated with 13aI therapy. A report from Sweden also failed to document any increased risk of thyroid cancer in patients who were treated with a3lI for hyperthyroidism [15]. Recent studies, in contrast, suggest that radiation increases K ras oncogene in thyroid cancers [47]. The aim of our investigation was to document whether ~31I therapy in patients with hyperthyroidism causes thyroid cancer and if any thyroid cancers that might develop are similar to those that occur sporadically. We analyzed our experience in our 7 of 373 unselected patients with thyroid cancer and those reported in the literature. Methods We retrospectively reviewed the records of 373 unselected patients with thyroid cancer: 77% of these patients had papil-